Origins of infantile Tay-Sachs disease alleles in a Cajun population

Abstract

The mechanisms responsible for the origin and maintenance of Tay-Sachs disease (TSD) alleles in the Ashkenazi Jewish population and others in which the occurrence of TSD is increased have yet to be delineated satisfactorily. As a model for studying these mechanisms, we evaluated five apparently unrelated Cajun families having members affected with TSD. The occurrence of TSD is elevated among Cajuns and preliminary studies suggest that the carrier frequency in the Cajun population may be increased over that of the general population. DNA sequence analysis revealed that, contrary to expectation, two different TSD alleles are present in the Cajun population: a {dollar}\beta{dollar}-hexosaminidase A {dollar}\alpha{dollar}-chain exon 11 insertion which is common among Jewish TSD carriers and an mRNA-negative allele which has not been described previously. Evaluation of pedigrees of 28 TSD carriers, identified by enzymatic and molecular screening of 95 relatives of the probands, revealed that the exon 11 insertion mutation has existed in the Cajun population since its establishment in the mid-1700's and most likely was introduced by members of a single family whose geographic origin is in France. Examination of these pedigrees for evidence of both increased fertility or survival among carriers of the insertion mutation compared to controls and preferential inheritance of this TSD allele produced no suggestion of heterozygote advantage. The presence of common ancestors among most of the exon 11 insertion carriers suggests that founder effect is responsible for the proliferation of this mutation among the Cajuns. The novel mutation has been in the Cajun population no more than four generations and appears confined to a single family. The Cajun population may well serve as a model for how founder effect and random genetic drift can result in the presence of two TSD alleles in a single population, one allele being found in the majority of carriers. This distribution of TSD alleles is similar to that seen in the Ashkenazi Jewish population. Of practical importance to the Cajun community is the likelihood that the exon 11 insertion mutation is widely distributed in southwest Louisiana and presents a significant public health problem within this community.